Heart Failure (HF) continues to be a leading cause of morbidity and mortality worldwide (1, 2). Despite advances in pharmacotherapy, deaths and hospitalizations continue to rise (2). Cardiac resynchronization therapy (CRT) is a non-pharmacologic therapy that has been proven to reduce morbidity and mortality in drug refractory symptomatic HF patients (3-6). Although CRT has proven its efficacy, it is unknown why only 70% of patients clinically benefit from CRT. Current hypotheses revolve around current imaging modalities'inability to optimally assess ventricular synchrony. Echocardiographic criteria have been used but operator dependence, non-standardization, and lack of reproducibility have limited its clinical value (7). Recent studies at our institutions using two noninvasive innovative imaging tools, electrocardiographic imaging (ECGI) and equilibrium radionuclide angiography (ERNA), provide high resolution, objective, highly reproducible ventricular synchrony measurements (8-12) - specifically, ECGI measuring electrical synchrony and ERNA measuring mechanical synchrony. However it is unknown whether ECGI and ERNA synchrony measures can successfully predict CRT responders. Therefore we hypothesize that ECGI and ERNA can be used to predict clinical responders to CRT by more accurately measuring and quantifying ventricular synchrony. This hypothesis will be tested by prospectively evaluating the use of ECGI and ERNA pre- and post-operatively in fifty patients undergoing CRT placement. Aim 1 will characterize and compare the parameters of synchrony as measured by ECGI and ERNA in individuals who qualify for CRT, specifically measuring parameters of ventricular synchrony including ECGI electrical synchrony index (Esyn) and ERNA-synchrony (S) and entropy (E) pre and post CRT implantation (8-12). We hypothesize that Esyn and E+S will accurately predict clinical response to CRT. Aim 2 will determine the specific relationship between ERNA sequence of phase progression and the sequence of myocardial activation, contraction, and conduction using ECGI epicardial activation maps. We hypothesize that ERNA sequence of phase progression will correlate with the epicardial activation maps of ECGI. Aim 3 will determine the use of ECGI and ERNA in guiding left ventricular (LV) catheter placement pre-operatively by analyzing the latest contracting segment by ERNA and latest activated segment by ECGI and identifying the site of delayed activation. We hypothesize that patients who have ECGI and ERNA driven LV lead optimization will have a higher success rate of clinical improvement as well as stronger indices of synchrony. PUBLIC HEALTH RELEVANCE: The results of our study will lead to better understanding of cardiac electrical and mechanical synchrony and the electrophysiologic mechanisms that affect response to CRT. This will be the first time that these two non-invasive strategies will be used together. By these aforementioned aims we may be able to increase the success rates of CRT past 70% and increase the quality of life for heart failure patients.